1. Field of the Invention
The present invention relates to a method for making optically active 3-aminopyrrolidine derivatives which are useful as raw materials for drugs and agrochemicals and to a method for making optically active 3-aminopyrrolidine-2,5-dione derivatives which are important intermediates thereof.
2. Description of the Related Art
Examples of the known methods for making optically active 3-aminopyrrolidine derivatives include a method in which racemic 1-benzyl-3-aminopyrrolidine is optically resolved by an optical active carboxylic acid. However, since the racemic 1-benzyl-3-aminopyrrolidine, which has been produced by a complex route, is further optically resolved, the method is expensive. Therefore, a method for making optically active 3-aminopyrrolidine derivatives inexpensively has been desired.
Examples of the known methods for making optically active 3-aminopyrrolidine-2,5-dione derivatives includes a method in which N-benzyloxycarbonyl-L-asparagine methyl ester is reacted with 0.95 equivalent of sodium hydroxide to produce (S)-3-benzyloxycarbonylaminopyrrolidine-2,5-dione, and then by way of the reaction described below, (S)-3-benzyloxycarbonylaminopyrrolidine is produced as disclosed in Tetrahedron; Asymmetry Vol. 3, 1239-1242 (1992). A method for producing a compound having a substituent in the first position is also disclosed in the same document, in which N-benzylation is carried out by the subsequent interphase reaction in the presence of a quaternary ammonium salt as shown below. 
Although the above method, which has high reaction selectivity, is superior in making optically active 3-aminopyrrolidine derivatives, it is difficult to employ the method for industrial use because (1) expensive L-asparagine is used as a starting material; (2) the number of process steps is increased, which is troublesome; and (3) a moisture-sensitive, expensive reducing agent (LiAlH4) is used.
It is an object of the present invention to provide methods for making optically active 3-aminopyrrolidine-2,5-dione derivatives and optically active 3-aminopyrrolidine derivatives from inexpensive raw materials, with a decreased number of process steps, in high yields, and with high optical purity.
The present inventors have carried out thorough research to overcome the difficulties described above and have achieved the present invention.
In one aspect of the present invention, a method for making an optically active 3-aminopyrrolidine-2,5-dione derivative represented by the following formula (3) includes cyclizing an optically active asparagine ester derivative represented by the following formula (1), an optically active isoasparagine ester derivative represented by the following formula (2) which is an isomer thereof, a mixture of these substances, or an acid salt of these substances: 
wherein R1 is a lower alkyl group having 1 to 4 carbon atoms, an aryl group, or an aralkyl group; each of R2 and R3 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an acyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, or an aralkylsulfonyl group, R2 and R3 being the same or different; R4 is an alkyl group having 1 to 3 carbon atoms; and the carbon atom with the asterisk * is an asymmetric center.
In another aspect of the present invention, a method for making an optically active 3-aminopyrrolidine derivative represented by the following formula (9) includes reducing an optically active 3-aminopyrrolidine-2,5-dione derivative represented by the formula (3): 
wherein R1, R2, R3, and the asterisk * are the same as those in the formula (1).
In another aspect of the present invention, a method for making an optically active 3-aminopyrrolidine derivative, in which the first position is unsubstituted, includes hydrogenolyzing an optically active 3-aminopyrrolidine derivative represented by the formula (9), wherein R1 is a substituted or unsubstituted benzyl group.
In the present invention, either the optically active asparagine ester derivative represented by the formula (1) or the optically active isoasparagine ester derivative represented by the formula (2) is referred to as an optically active asparagine ester derivative. Additionally, either an optically active asparagine derivative represented by the formula (6) below or an optically active asparagine derivative represented by the formula (7) below which is an isomer thereof is referred to as an optically active asparagine derivative.
These compounds also include optically active substances in which either the L-form (S-form) or the D-form (R-form) is in excess and also include an acid salt thereof.
The optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3), the optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9), and the optically active 3-aminopyrrolidine derivative in which the first position is unsubstituted also include optically active substances in which either the L-form (S-form) or the D-form (R-form) is in excess and also include an acid salt thereof. The optical purity of the optically active substances is !preferably 80% e.e. or more, and more preferably 90% e.e. or more.
In the present invention, the optically active asparagine ester derivative represented by the formula (1) or (2), or an acid salt thereof is cyclized to produce the optically active 3-aminopyrrolidine-2,5-dione derivative represented by the formula (3). In such a method, it is not necessary to protect or deprotect an amino group in the third position, and also it is possible to produce an optically active 3-aminopyrrolidine-2,5-dione derivative from the optically active asparagine ester derivative represented by the formula (1) or (2) with a decreased number of process steps, in high yields, and with high optical purity.
In the formula (1), R1 is preferably a lower alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group, and is more preferably a substituted or unsubstituted benzyl group. Each of R2 and R3 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an acyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, or an aralkylsulfonyl group, and R2 and R3 may be the same or different as described above. When R2 is any one of an acyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, and an aralkylsulfonyl group, R3 is preferably a hydrogen atom. Preferably, as the aryl group, a substituted or unsubstituted phenyl group is selected, and as the aralkyl group, a substituted or unsubstituted benzyl group is selected.
Each of the compounds represented by the formula (1) and (2) may be used alone or the compounds may be used as a mixture thereof in any mixing ratio. Preferably, the compounds have an optical purity of 90% e.e. or more.
The cyclization may be carried out in an organic solvent or in water. Preferably, the cyclization is carried out in an aqueous solution in which an organic solvent and water are mixed. The pH of the reaction liquid is preferably 3 to 8, more preferably 5 to 7.5, and most preferably 6 to 7. The pH may be adjusted after an acid salt of the optically active asparagine ester derivative is dissolved into an aqueous solution. Alternatively, after the optically active asparagine ester derivative is dissolved in the aqueous solution in which the pH is preliminarily adjusted, the pH may be finely adjusted again. As the organic solvent, although any compound which is inert in the reaction and which is dissolved in water homogeneously may be used, preferably, a lower alcohol, such as methanol or ethanol, or a water-soluble ether, such as tetrahydrofuran or glyme, is used, and more preferably, methanol is used.
Preferably, the pH of the reaction liquid is adjusted by adding an alkali metal salt to the reaction liquid because the yield and the optical purity of the optically active 3-aminopyrrolidine-2,5-dione derivative produced are further increased. As the alkali metal salt, an alkali metal organic acid salt, such as sodium formate, potassium formate, sodium acetate, or potassium acetate; an alkali metal carbonate, such as sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate, such as sodium hydrogencarbonate or potassium hydrogencarbonate; or a mixture thereof may be used. Preferably, sodium acetate, sodium carbonate, or sodium hydrogencarbonate is used, and more preferably, sodium hydrogencarbonate is used.
The reaction temperature is preferably in the range of 0 to 80xc2x0 C., and more preferably 20 to 60xc2x0 C. The reaction time, which depends on the type of starting material and on the reaction conditions, is 0.1 to 30 hours. Although the racemization rate in the cyclizing reaction slightly differs depending on the pH of the reaction mixture, the reaction time, the type of alkali metal salt to be added, etc., by using the production method described above, it is possible to produce the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) having an optical purity of 80% e.e. or more. If the optically active asparagine ester derivative used represented by the formula (1) or (2) has an optical purity of 95% e.e. or more, it is possible to obtain the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) having an optical purity of 90% e.e. or more.
In order to isolate the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative from the reaction mixture, any known method may be used. For example, the reaction mixture is adjusted to be weakly basic, and then extraction is performed using an organic solvent. As the organic solvent, although any compound which is stable during the extraction may be used, for example, toluene or chloroform is preferably used. When the amino group in the third position is basic in the compound represented by the formula (3), it is possible to isolate as an acid salt thereof. When the substituent in the first position in the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) is an aryl group or an aralkyl group, e.g., optically active 3-amino-1-benzylpyrrolidine-2,5-dione, since extraction is easily performed using the organic solvent, isolation and purification are facilitated. The concentrate obtained by subjecting the extract to vacuum concentration may be used as it is in the subsequent step.
By reducing the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) thus produced, it is possible to produce the optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9).
As the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative used represented by the formula (3), the one which is isolated and purified, the concentrate of the extract, or an acid salt thereof may be used. The compound preferably has an optical purity of 81% e.e. or more.
As the reaction solvent used an ether, such as tetrahydrofuran, glyme, diglyme, or butanol, may be used. Preferably, tetrahydrofuran, glyme, or diglyme is used, and more preferably, glyme is used.
As the reducing agent, aluminum lithium hydride or a boron hydride may be used. Preferably, the boron hydride which is chemically stable and easy to handle is used. Preferred examples of the boron hydrides include diborane, borane diethyl ether, borane dimethyl sulfide, and sodium borohydride. When sodium borohydride is used, an activating reagent, such as sulfuric acid or trifluoroboron, may be added thereto. The reaction temperature is preferably in the range of xe2x88x9220 to 80xc2x0 C., and more preferably in the range of xe2x88x9210 to 30xc2x0 C. The reaction time, which depends on the conditions, is usually 3 to 20 hours.
After the reaction is complete, the produced optically active 1-substituted-3-aminopyrrolidine derivative may be isolated by a known method. For example, after methanol is added to the reaction mixture, concentration is performed to decompose and remove excess borane. The concentrate is dissolved in water and is adjusted to be basic, and extraction is performed using chloroform, and thus the optically active 1-substituted-3-aminopyrrolidine derivative is extracted in a chloroform layer. By concentrating the resultant chloroform layer, the optically active 3-aminopyrrolidine derivative is obtained. By using the production method described above, the optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9) having an optical purity of 80% e.e. or more can be obtained. If the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) used has an optical purity of 92% e.e. or more, it is possible to obtain the optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9) having an optical purity of 90% e.e.
In the optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9) thus obtained, when the substituent in the first position is a substituted or unsubstituted benzyl group, by performing hydrogenolysis in the presence of a noble metal catalyst, an optically active 3-aminopyrrolidine derivative in which the first position is unsubstituted is produced.
As the noble metal catalyst, palladium supported by activated carbon is preferably used. The hydrogen pressure is preferably 0.1 to 5 MPa and more preferably 0.5 to 1 MPa.
The hydrogenolysis is preferably performed In a solvent. As the solvent, an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran, or an aromatic hydrocarbon such as toluene is preferably used. More preferably, methanol or ethanol is used.
The reaction temperature is preferably in the range of 20 to 100xc2x0 C., and more preferably in the range of 40 to 70xc2x0 C. The reaction time, which depends on the conditions, is usually 3 to 20 hours.
After the reaction is complete, the produced optically active 3-aminopyrrolidine derivative may be isolated by a known method. For example, after the reaction mixture is filtered to remove the noble metal catalyst, concentration and distillation are performed, and thus the optically active 3-aminopyrrolidine derivative is obtained. By using the production method described above, the optically active 3-aminopyrrolidine derivative having an optical purity of 80% e.e. or more can be obtained.
In accordance with the methods described above, it is possible to produce optically active 3-aminopyrrolidine derivatives and optically active 3-aminopyrrolidine-2,5-dione derivatives which are the intermediates thereof from the optically active asparagine ester derivative represented by the formula (1) or (2) with a decreased number of process steps, in high yields, and with high optical purity. In the reduction reaction, a boron hydride which is chemically stable and easy to handle can be used as the reducing agent, which is also advantageous.
In the present invention, the optically active asparagine ester derivative represented by the formula (1) or (2) can be produced using inexpensive optically active aspartic acid as a starting material, which is also advantageous. In the present invention, although the optically active aspartate ester derivative represented by the formula (1) or (2) may be produced using a raw material other than the optically active aspartic acid, the inexpensive optically active aspartic acid is preferably used as the starting material in view of cost efficiency.
A method for producing the optically active asparagine ester derivative represented by the formula (1) or (2) from the optically active aspartic acid is not particularly limited. One embodiment will be described below. 
Using the optically active aspartic acid as the starting material, an optically active aspartic anhydride represented by the following formula (4) is produced: 
wherein each of R5 and R6 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an acyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, or an aralkylsulfonyl group, R5 and R6 being the same or different. The optically active aspartic acid preferably has an optical purity of 99% e.e. or more.
The optically active aspartic anhydride can be produced by reacting the optically active aspartic acid with an organic acid anhydride. As the organic acid anhydride, a monoacid anhydride, such as formic anhydride, acetic anhydride, or propionic anhydride, or a heteroacid anhydride, such as formic acetic anhydride may be used. Preferably, acetic anhydride or formic acetic anhydride is used, and more preferably, formic acetic anhydride is used.
Preferred examples of the optically active aspartic anhydrides represented by the formula (4) include dialkyl derivatives, such as N-dimethylaspartic anhydride and N-methylbenzylaspartic anhydride; N-acyl derivatives, such as N-formylaspartic anhydride, N-acetylaspartic anhydride, and N-propionylaspartic anhydride; and sulfonyl derivatives, such as N-benzenesulfonylaspartic anhydride. Among these are preferably N-acyl aspartic anhydrides, such as N-formylaspartic anhydride, N-acetylaspartic anhydride, and N-propionylaspartic anhydride because the N-acylaspartic anhydride can be produced in only one step from the optically active aspartic acid and the organic acid anhydride by the reaction described above. Furthermore, since the N-acyl group can be easily deprotected as described below, the N-acylaspartic anhydride is more preferably used when the 3-aminopyrrolidine-2,5-dione derivative in which the amino group in the third position is unsubstituted is produced. More preferably, N-formylaspartic anhydride or N-acetylaspartic anhydride is used, and most preferably, N-formylaspartic anhydride is used.
A known method may be used for the reaction. For example, formic acetic anhydride, which has been preliminarily formed by mixing acetic anhydride and formic acid, and L-aspartic acid are reacted with each other while stirring at 50 to 70xc2x0 C. for 2 to 5 hours, followed by cooling to room temperature, and toluene is added thereto to crystallize N-formyl-L-aspartic anhydride, and then filtration is performed. In such a step, the reaction smoothly proceeds even without adding an acid catalyst, and under the normal conditions, racemization does not substantially occur.
Next, the optically active aspartic anhydride represented by the formula (4) is reacted with an amine represented by the following formula (5):
R1xe2x80x94NH2xe2x80x83xe2x80x83(5)
wherein R1 is the same as that in the formula (1), to produce an optically active asparagine derivative represented by the following formula (6) or (7), or an acid salt thereof: 
wherein R1 and the asterisk * are the same as those in the formula (1), and R5 and R6 are the same as those in the formula (4). As the optically active N-aspartic anhydride represented by the formula (4), although either the L-form or the D-form may be used depending on the application, the optical purity is preferably 98% e.e. or more.
As the amine represented by the formula (5), a lower alkylamine having 1 to 4 carbon atoms, such as methylamine or propylamine, an arylamine, such as aniline or anisidine, or an aralkylamine, such as benzylamine, may be used. When the produced optically active asparagine derivative represented by the formula (6) or (7) is continuously used as the raw material for the cyclization and the reduction reaction, the amine may be selected according to the relevant compound. In view of the extraction efficiency by the organic solvent from the reaction system, the deprotection in the subsequent step, etc., benzylamine is preferably used. The amount of the amine used is preferably 0.8 to 5 equivalent, and more preferably 0.99 to 1.5 equivalent relative to the optically active aspartic anhydride represented by the formula (4). If the amount of the amine used is in the above range, both the reaction yield and the cost efficiency are increased. If a large amount of amine is used, the cost efficiency is decreased, and the optically active asparagine derivative represented by the formula (6) or (7) is also easily racemized, which is disadvantageous.
In the reaction, dilution is preferably carried out using an organic solvent. As the solvent, any compound which does not react with the substrate may be used. Examples of the solvent include alcohols, such as ethanol; ethers, such as tetrahydrofuran; aromatic hydrocarbons, such as toluene; alkyl halides, such as chloroform; ketones, such as acetone; carboxylic acids, such as acetic acid; and esters, such as butyl acetate. The preferred solvent is tetrahydrofuran or acetic acid. These solvents may be used alone or as a mixture thereof. Although the amount of the solvent used is not particularly limited as long as the content allows the stirring operation, in view of cost efficiency, the content is usually set so that the substrate content is approximately 5 to 30% by weight. The reaction temperature is preferably 0 to 60xc2x0 C., and more preferably 10 to 40xc2x0 C. Since the racemization may also occur if the reaction temperature is increased, the reaction is preferably carried out in the range described above. The reaction time, which depends on the conditions, is usually 1 to 20 hours.
The resultant optically active asparagine derivative represented by the formula (6) or (7) is concentrated or cooled, and then is isolated by filtering the precipitate. The concentrate may be used as it is for the esterification in the subsequent step. By using the method described above, the optically active asparagine derivative represented by the formula (6) or (7) having an optical purity of 90% e.e. or more can be obtained.
Next, the optically active asparagine derivative represented by the formula (6) or (7) is reacted with an alcohol represented by the following formula (8):
R4OHxe2x80x83xe2x80x83(8)
wherein R4 is an alkyl group having 1 to 3 carbon atoms, to produce the optically active aspartate ester derivative represented by the formula (1) or (2). The optically active asparagine derivative represented by the formula (6) may be used alone, the optically active isoasparagine derivative represented by the formula (7) may be used alone, or a mixture of both may be used. The optically active asparagine derivative preferably has an optical purity of 95% e.e. or more.
As the alcohol represented by the formula (8), methanol, ethanol, propanol and isopropanol may be used. Preferably, methanol or ethanol is used, and more preferably, methanol is used. In view of the reaction yield and the reaction time, the amount of the alcohol to be used is preferably 3 to 5 molar times the amount of the optically active asparagine derivative represented by the formula (6) or (7). When the alcohol is also used as a reaction solvent, it is preferably 14 to 30 molar times, and more preferably 15 to 20 molar times. The alcohol may be mixed with an organic solvent. As the organic solvent, an ether such as tetrahydrofuran, an aromatic hydrocarbon such as toluene, a ketone such as acetone, or a halide such as chloroform may be used.
When the esterification is performed, an acid is preferably added thereto. As the concomitant acid, a mineral acid, such as hydrochloric acid or sulfuric acid; a sulfonic acid, such as toluenesulfonic acid; a Lewis acid, such as ferric chloride or zinc chloride, a cation exchange resin, or the like may be used. In such a case, preferably, the reaction is carried out while removing water produced by the esterification from the system. Although the required amount of the acid to be used is the sum of the amount for neutralizing the amino group in the optically active asparagine ester derivative represented by the formula (1) or (2) to be produced and the amount for catalyzing the esterification, in view of the reaction rate, the cost efficiency, and the load in the purification process, the amount of the acid is preferably 1.02 to 1.10 molar times the amount of the optically active asparagine ester derivative.
Instead of the acid, thionyl chloride may be used. In such a case, since water is not produced in the esterification, the reaction process is simplified and the reaction yield is also improved, thus being particularly advantageous. The amount of thionyl chloride to be used is preferably 0.9 to 2.5 molar times, more preferably 1.1 to 2.0 molar times, the amount of the optically active asparagine ester derivative. Since hydrochloric acid by-produced in the reaction and excess thionyl chloride can be removed from the system by simple process, such as concentration, it is possible to use a large amount of thionyl chloride in order to increase the reaction rate.
The reaction temperature is preferably 0 to 80xc2x0 C., and more preferably 10 to 40xc2x0 C. Within such a range, the reaction yield is increased and the racemization is inhibited. The reaction time, which depends on the conditions, is usually 1 to 20 hours.
The resultant optically active asparagine ester derivative represented by the formula (1) or (2), or an acid salt thereof is isolated by a conventional method. When a large amount of alcohol is used, vacuum concentration is performed to remove the alcohol and the acid with a low boiling point or excess thionyl chloride, and then an organic solvent, such as tetrahydrofuran, is added again, followed by stirring. The precipitated crystal is filtered or vacuum concentration is performed, followed by drying. Thus, the acid salt of the optically active aspartate ester derivative represented by the formula (1) or (2) is isolated. Additionally, the concentrate obtained by vacuum concentration may be used as it is as a raw material for the cyclization.
By the method described above, it is possible to produce the optically active asparagine ester derivative represented by the formula (1) or (2) having an optical purity of 90% e.e. or more, or an acid salt thereof. If the optically active asparagine derivative represented by the formula (6) or (7) which has been used has an optical purity of 98% e.e. or more, it is possible to obtain the optically active asparagine ester derivative represented by the formula (1) or (2) having an optical purity of 95% e.e. or more. Additionally, although the produced acid salt of the optically active asparagine ester derivative represented by the formula (1) or (2) may be neutralized to form a free optically active asparagine ester derivative, preferably it is preserved as the acid salt since the free optically active asparagine ester derivative is chemically unstable.
In the esterification, when R5 is an acyl group and R6 is a hydrogen atom in the optically active asparagine derivative represented by the formula (6) or (7), i.e., in the case of N-acylasparagine ester derivative, the deprotection of the N-acyl group can be carried out simultaneously with the esterification, which is, therefore, particularly advantageous when a 3-aminopyrrolidine-2,5-dione derivative in which the amino group in the third position is unsubstituted is produced.
By using the optically active asparagine ester derivative represented by the formula (1) or (2) thus obtained as the raw material for the reaction in the present invention, it is possible to produce optically active 3-aminopyrrolidine derivatives and optically active 3-aminopyrrolidine-2,5-dione derivatives which are the intermediates thereof from the inexpensive optically active aspartic acid as the raw material, with a decreased number of process steps, in high yields, and with high optical purity.
The present invention will be described more in detail based on the examples below. However, the present invention is not limited thereto. Additionally, the chemical purity of the optically active asparagine ester derivative represented by the formula (1) or (2) was determined by HPLC. After hydrolysis and conversion to a tartaric acid derivative according to the formula below, the optical purity was determined by HPLC. 
The optical purity was calculated according to the following formula:       Optical    ⁢          xe2x80x83        ⁢    Purity    ⁢          xe2x80x83        ⁢          (              %        ⁢                  xe2x80x83                ⁢        ee            )        =                    X        -        Y                    X        +        Y              xc3x97    100  
X: L-derivative (or D-derivative)
Y: D-derivative (or L-derivative)
The optical purity of the 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3) was determined by HPLC analysis after the chemical derivation according to the following formula: 
Additionally, the optical purity of the 1-substituted-3-aminopyrrolidine derivative was determined in a manner similar to the above. The reagents used in the examples were commercially available extra-pure reagents.